The invention relates to methods for the production of L-carnitine.
Carnitine (vitamin Bt; 3-hydroxy-4-trimethylammonio-butanoate) is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy. It is used as a nutritional supplement. Carnitine exists in two stereoisomers. The biologically active form is L-carnitine, whilst its enantiomer, D-carnitine, is biologically inactive. When producing L-carnitine in an industrial process, it is desirable to produce the biologically active L-form in high purity.
Various methods were described for the industrial production of L-carnitine. Microbiological processes are known, in which L-carnitine is produced directly by bacteria. In other processes, a racemate is produced by organic synthesis and separated subsequently into enantiomers.
Further, attempts have been made to synthesize L-carnitine directly from chiral precursors. A group of potential precursors are chiral cyclic lactones. Since methods for obtaining chiral lactones are known in principle, L-carnitine is available upon hydrolysis of the lactone ring.
U.S. Pat. No. 5,473,104 discloses a process for the preparation of L-carnitine from (S)-3-hydroxybutyrolactone. The process is a two-step process, wherein in a first step (S)-3-hydroxybutyrolactone is converted into the corresponding hydroxy-activated lactone, whilst maintaining the ring structure. In a second step, the ring of the activated lactone is opened and the trimethylammonium group is introduced with trimethylamine. Altogether, the reaction is relatively complicated because it requires the activation of an intermediate with harsh chemicals.
CH 680 588 A5 discloses a process for producing L-carnitine from a 3-lactone precursor, wherein a chiral 2-oxetanone is converted into L-carnitine in a two-step process. In a first step, 4-(chloromethyl)-2-oxetanone is subjected to a hydrolysis step, in which the ring is opened and 4-chloro-3-hydroxybutyric acid is obtained. In a subsequent step, the acid is converted into L-carnitine with trimethylamine. However, the production of chiral β-lactones requires relatively complicated heavy metal catalysts and the yields are often not sufficient.
Nelson & Spencer (J. Org. Chem. 2000, 65, 1227-1230) disclose a process for obtaining enantiomerically enriched β-lactones from β-lactone racemates by enzymatic resolution with lipases. The substrates used are various alkyl- and aryl-β-lactone racemates. As summarized in Table 1, the yields are only sufficient for a limited number of reactions. The enantioselectivity depends strongly on the substituents of the β-lactone and the enantiomeric yield for the small substituent methyl is very low (table 1). The reactions require organic solvents, such as benzyl alcohol, which is not desirable for industrial applications for environmental reasons. The reaction times are relatively long (mostly 72 hours).
US 2006/0046286 discloses methods for obtaining chiral β-butyrolactones and 3-hydroxycarboxylic acid esters by enzymatic esterification from β-lactones. As for Nelson & Spencer, the use of lipases is suggested. The reactions require organic solvents, such as toluene, and relatively long reaction times for about 16 hours. The substrate is β-butyrolactone. In most experiments, the substrate is not a racemate, but optically active (R)-β-butyrolactone. The specific reactions mostly yield (R)-β-butyrolactone at enhanced enantiomeric purity, whereas (S)-3-hydroxybutyric acid esters, if at all, are obtained only in relatively low amounts (examples 1, 6, 7).
Since enantiomerically pure L-carnitine is an important industrial product, it would be desirable to provide further efficient processes for its production. Specifically, it would be desirable to provide processes for the production of L-carnitine in a relatively simple manner at a high total yield and enantiomeric yield.